Bicyclo(3.3.0)Octene derivatives

ABSTRACT

There are disclosed a bicyclo[3.3.0]octene derivatives having the following formula: ##STR1## wherein R 1  : a straight, branched or cyclic alkyl group or alkenyl group each having 5 to 10 carbon atoms; 
     R 2  and R 3  : each represent a hydrogen atom or a protective group of a hydroxy group; and 
     R 4  : --CH═CH--(CH 2 ) 2  --COOR 5  or --CH 2  R 6  ; where 
     R 5  : a hydrogen atom or an alkyl group; and 
     R 6  : a hydroxy group, an acetyloxy group or a butenyl group, 
     and process for producing the same. These compounds and the process for producing them are available for producing a 9(0)-methano-Δ 6  (9α)-PGI 1 .

This is a continuation, division, of application Ser. No. 641,587, filedAug. 17, 1984, Pat. No. 4,681,951.

BACKGROUND OF THE INVENTION

This invention relates to a bicyclo[3.3.0]octene derivative and aprocess for producing the same.

9(0)-methano-Δ⁶(9α) -PGI₁ a potent platelet aggregation inhibitingaction. For example, its action is comparable to chemically unstablePGI₂, when human platelet is employed, and it is a compound which can beutilized as a therapeutic or preventive for various diseases ofcirculatory organs (see the test examples shown below).

In the prior art, as the process for producing 9(0)-methano-Δ⁶(9α)-PGI₁, there have been known (a) the process in which it is producedthrough the 14 steps using PGE₂ as the starting material [PreliminaryText for Lectures in 103rd Annual Meeting in Pharmaceutical Society ofJapan, p. 156, (1983)] and (b) the process in which it is produced from1,3-cyclooctadiene through 19 steps [Preliminary Text for Lectures in103rd Annual Meeting in Pharmaceutical Society of Japan, p. 157,(1983)]. The former process has the drawback that the starting materialis expensive, while the latter process that the desired product isformed as a racemic mixture. Further, both processes (a) and (b) arealso disadvantageously very low in the overall yield.

SUMMARY OF THE INVENTION

The present inventors have studied extensively to produce9(0)-methano-Δ⁶(9α) -PGI₁ from a cheap starting material at good yieldand with optical activity as well as steric configuration specificity,and consequently found that the compound of the present invention andthe process for producing the same can be an important intermediate anda process for achieving the object to accomplish the present invention.

This invention concerns a compound of the formula: ##STR2## wherein R¹ :a straight, branched or cyclic alkyl group or alkenyl group each having5 to 10 carbon atoms;

R² and R³ : each represent a hydrogen atom or a protective group of ahydroxy group; and

R⁴ : --CHO, --CH═CH--(CH₂)₂ --COOR⁵ or --CH₂ R⁶ ;

where

R⁵ : a hydrogen atom or an alkyl group; and

R⁶ : a hydroxy group, an acetyloxy group or a butenyl group,

and a process for producing the same.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The bicyclo[3.3.0]octene derivative represented by the above formula [I]of this invention can be led to 9(0)-methano-Δ⁶(9α)-PGI₁ and derivativesthereof as follows: Namely, among the above bicyclo[3.3.0]octenederivatives, bicyclo[3.3.0]octenylaldehyde derivatives which are R⁴being --CHO can be led to 9(0)-methano-Δ⁶(9α) -PGI₁ by subjecting themto elongation reaction of α-chain by using Wittig reagent which isprepared by 3-carboxypropyltriphenylphosphonium bromide and a base,subjecting a hydroxy group to deprotection reaction, then subjecting adouble bond selectively to reduction and thereafter subjecting an esterto hydrolysis; (4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octenederivatives which are R⁴ being --CH═CH--(CH₂)₂ --COOR⁶ can be led thesame by subjecting them to elongation reaction of α-chain, subjecting ahydroxy group to deprotection reaction and thereafter subjecting anester to hydrolysis; and bicyclo[3.3.0]octene derivatives which have R⁴being --CH₂ R⁵ can be led the same by subjecting them to hydrationreaction, then subjecting a hydroxy group to deprotection reaction, andthereafter subjecting to oxdation reaction (see the following Referenceexamples).

The protective group of hydroxy group in this invention may include, forR², a tetrahydropyranyl group, a methoxymethyl group, a4-methoxytetrahydropyranyl group, a 1-ethoxyethyl group, a1-methyl-1-methoxyethyl group, a t-butyldimethylsilyl group, adiphenyl-t-butylsilyl group, a benzoyl group, an acetyl group, etc. and,for R³, a t-butyldimethylsilyl group, a benzoyl group, an acetyl group,a tetrahydropyranyl group, a methoxymethyl group, a4-methoxytetrahydropyranyl group, a 1-ethoxyethyl group, a1-methyl-1-methoxyethyl group, a diphenyl-t-butylsilyl group, etc.

The bicyclo[3.3.0]octene derivative represented by the above formula [I]can be produced according to the reaction schemes as shown below.

In the compounds of the present invention,(4,'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivatives[I-c] can be prepared following the reaction schemes shown below:##STR3## wherein R¹, R², R³ and R⁵ are the same as defined above.

[The first step]

This step produces an allyl cyclopentylidene derivative represented bythe formula [III] by methylenation of an allyl cyclopentanone derivativerepresented by the above formula [II].

The allyl cyclopentanone derivative which is employed as the startingmaterial of this step is produced by reacting a cyclopentenonerepresented by the formula [V]: ##STR4## wherein R² represents aprotective group of a hydroxy group, with an organic copper compoundrepresented by the formula [VI]: ##STR5## wherein R¹ is the same meaningas defined above; R³ represents a protective of a hydroxy group; and Yrepresents a group of ##STR6## a phenylthio group or a 1-pentynyl group(see Japanese Provisional Patent Publication No. 171965/1982).

Examples of the thus obtained compounds may be{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-1'-transoctenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-4'-methyl-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-tetrahydropyranyloxy-4'-methyl-1'-trans-octenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-(1'-ethoxyethyloxy)-1'-transoctenyl]-4(R)-(1'-ethyoxyethyloxy)-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-(1'-ethoxyethyloxy)-3'-cyclopentyl-1'-trans-propenyl]-4(R)-(1'-ethoxyethyloxy)-1-cyclopentanone},{2(R)-allyl-3(R)-[3'(S)-(1'-ethoxyethyloxy)-4'-methyl-1'-trans-octenyl)-4(R)-(1'-ethoxyethyloxy)-1-cyclo-pentanone)and the like.

The methylenation in this step may be carried out by use of a mixedreagent of methylene bromide-titanium tetrachloride-zinc [L. Lombardo,Tetrahedron Lett., 23, 4293 (1982)] or Johnson reagent [C. R. Johnson,J. R. Shanklin, R. A. Kirchoff, J. Am. Chem. Soc., 95, 6462 (1973)].

The reaction should desirably be carried out in a solvent, for example,a solvent mixture such as a halogenic solvent (e.g. methylenechloride) - an ether solvent (e.g. tetrahydrofuran) in the case of usingthe former reagent, while an ether solvent in the case of the latterreagent.

The reaction can proceed smoothly at -80° C. to 60° C., but roomtemperature is preferred because the reaction can be carried out withoutheating or cooling.

[The second step]

This step produces a hydroxymethyl cyclopentane derivative representedby the above formula [IV] by hydration of an allyl cyclopentylidenederivative represented by the above formula [III].

The hydration reaction in this step is conducted out by hydroborationand oxidation. In carrying out hydroboration, there may be employed ahydroborating reagent such as 9-BBN (9-borabicyclo[3.3.1]nonane),disiamylborane, thexylborane, etc. The amount of the hydroborating agentused may be generally 1 to 3 equivalent.

The reaction is desired to be carried out in a solvent, preferably anether type solvent such as tetrahydrofuran, diglyme, diethylether, etc.

The reaction proceeds smoothly at -25° C. to room temperature.

Further, this step carries out oxidation of the product subsequent tothe hydroboration without isolation thereof. The oxidation may becarried out by use of an oxidizing agent such as an alkaline hydrogenperoxide, an amine oxide, oxygen, peracid, etc. The amount of theoxidizing agent employed may be 5 to 15 equivalents.

The reaction proceeds smoothly at room temperature to 60° C.

In this step, the compound formed by hydroboration with the use of, forexample, 9-BBN may be estimated to have a formula as shown below:##STR7##

[The third step]

This step produces a bicyclo[3.3.0]octenylaldehyde derivativerepresented by the above formula [I-b] by oxidation and dehydration ofthe hydroxymethyl cyclopentane derivative represented by the aboveformula [IV] obtained by the above second step.

In carrying out oxidation, it is possible to use adimethylsulfoxide-oxalyl chloride, dimethylsulfoxidepyridine complex ofsulfur trioxide, etc. The amount of the oxidizing agent employed may begenerally 1 to 5 equivalents.

The reaction is desired to be carried out in a solvent, for example, ahalogenated hydrocarbon such as methylene chloride.

The reaction can proceed smoothly at a temperature, which may differdepending on the oxidizing agent employed, but generally at -70° C. toroom temperature.

For obtaining the oxidized product in this step, a tertiary amine suchas triethylamine, diisopropylethylamine, etc. is added into the reactionproduct and treatment is carried out at -70° C. to room temperature.

Further, this step carries out dehydration of the obtained productsubsequent to the oxidation without isolation thereof.

Dehydration is required to be carried out in the presence of an acidiccatalyst. As the acidic catalyst, an acid-ammonium salt is available. Anacid-ammonium salt can be formed from an acid and an amine. The acidavailable may be exemplified by trifluoroacetic acid, toluenesulfonicacid, camphorsulonic acid, acetic acid, etc. The amine available may beexemplified by dibenzylamine, diethylamine, dimethylamine,diisopropylamine, piperidine, pyrrolidine, piperazine, etc. These acidsand amines may appropriately be selected and combined to be provided foruse. Above all, the catalyst comprising a combination of trifluoroaceticacid and dibenzylamine is preferred on account of good yield of thedesired product. The amount of the catalyst employed may be about 0.2equivalent, but it is preferred to employ about one equivalent in orderto proceed rapidly the reaction.

The reaction is desired to be carried out in a solvent, for example, anaromatic hydrocarbon such as benzene, toluene, xylene, etc.

The reaction temperature may be.selected within the range from roomtemperature to 100° C., but preferably within the range from 50° C. to70° C. in order to carry out the reaction smoothly.

[The fourth step]

This step produces a(4'-alkoxycarbonyl-1'-alkenyl)-cisbicyclo[3.3.0]octene derivativerepresented by the above formula [I-c] by reacting thebicyclo[3.3.0]octenylaldehyde derivative represented by the aboveformula [I-b] obtained by the above third step with 3-carboxypropyltriphenyl phosphonium halide represented by the formula: ##STR8##wherein R⁷ is an alkyl group or an aryl group, and X is a halogen atom,in the presence of a base.

This step is required to be carried out in the presence of a base. Thebase may include potassium t-butoxide, butyl lithium, sodium salt ofdimethylsulfoxide, etc. For carrying out the reaction with goodefficiency, it is preferred to employ potassium t-butoxide. The amountof the base employed may be generally 1 to 1.2 equivalent based on theabove 3-carboxypropyl triphenyl phosphonium halide which is employed asone of the starting material. Preferable example of the 3-carboxypropyltriphenyl phosphonium halide is 3-carboxypropyl triphenyl phosphoniumbromide.

The reaction may be carried out preferably in an ether solvent such astetrahydrofuran, dimethoxyethane, diethyl ether, etc. The solvent is notparticularly limited, provided that it does not interfere with thereaction.

The reaction temperature may be selected within the range from 0° C. to50° C., at which the reaction can proceed smoothly.

The compound obtained in this step is formed generally as a freecarboxylic acid, but it can be isolated as an ester by use of thecondition of diazomethane or alkylhalide-diazabicycloundecene-acetonitrile for the reactions in thesubsequent step et seq. Conversion to ester may be conducted accordingto the method easily done by those skilled in the art.

[The fifth step]

This step produces a bicyclo[3.3.0]octene derivative represented by theabove formula [I-a] in which only the disubstituted olefin of α-chain isselectively reduced by catalytic reduction of the(4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivativerepresented by the formula [I-c] obtained in the above fourth step.

The available catalysts include palladium catalysts such aspalladium-carbon, palladium black, etc., Wilkinson catalysts, platinum,nickel, etc. For carring out the reaction with good efficiency, it ispreferred to employ Wilkinson catalyst. The catalyst may be sufficientlyemployed in the so-called catalytic amount.

In practicing this step, hydrogen may be allowed to react with thecompound under normal pressure or under pressurization.

The reaction may be carried out preferably in a solvent, for example, analcohol solvent such as methanol, ethanol, etc. or an ester solvent suchas ethyl acetate, etc.

The reaction can proceed smoothly at a temperature selected within therange from -25° C. to 60° C.

The (4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivativeof this invention has a asymmetric carbon atom in the molecule, and thepresent invention includes compounds of a R-configuration,S-configuration and a mixture of a volumtary ratio thereof with regardto the asymmetric carbon atom.

Further, in the above formula [I], the bicyclo[3.3.0]octene derivativesin which R⁴ being --CH₂ R⁶ represented by the formula [I-f] can beproduced by subjecting bicyclo[3.3.0]octenyl aldehyde derivativerepresented by the above formula [I-b] to the reaction step as mentionedbelow: ##STR9##

[The first step]

This step produces a bicyclo[3.3.0]octenyl methyl alcohol derivaticerepresented by the above formula [I-d] by reduction of thebicyclo[3.3.0]octenylaldehyde derivative represented by the aboveformula [I-b].

In the bicyclo[3.3.0]octnylaldehyde derivatives, the compounds in whichR¹ are straight or branched alkyl or alkenyl group are preparedaccording to the method as described in Preliminary text for lectures in104th annual meeting in Pharmaceutical Society of Japan (1984), p. 282,and the compound in which R¹ are cylcic alkyl or alkenyl are preparedaccording to the same method as mentioned above.

Reduction is required to be carried out in the presence of a reducingagent. As the reducing agent, diisobutylaluminum hydride, sodiumborohydride, lithium aluminumhydride and the like are available. Theamount of the reducing agent employed may be about one equivalent orslightly excess amount based on the bicyclo[3.3.0]octenylaldehydederivative represented by the above formula [I-b].

The reaction should desirably be conducted in a solvent, for example, analcohol solvent such as methanol, ethanol, etc., an ether solvent suchas diethyl ether, tetrahydrofuran, etc., an aromatic solvent such asbenzene, toluene, etc., and a halogenic solvent such as methylenechloride, chloroform, etc. The solvent may optionally be selected due tothe reducing agent to be used. The reaction can proceed smoothly at-100° to 50° C.

[The second step]

This step produces a bicyclo[3.3.0]octenylmethylacetate derivativerepresented by the above formula [I-e] by acetylation of thebicyclo[3.3.0]octenylmethyl alcohol derivative represented by the aboveformula [I-d] obtained in the above first step.

In carrying out acetylation, it is possible to use an acetic anhydridewhich is generally employed this type of reaction.

Furhter, in carrying out this step, it is possible to employ a catalystsuch as pyridine, 4-dimethylaminopyridine, etc.

The reaction should desirably be conducted in a solvent, for example, anaromatic solvent such as benzene, toluene, etc., an ether solvent suchas diethyl ether, tetrahydrofuran, etc., and a halogenic solvent such asmethylene chloride, etc.

The reaction can proceed smoothly at -25° to 100° C.

[The third step]

This step produces a pentenylbicyclo[3.3.0]octene derivative representedby the above formula [I-f] by reacting the bicyclo[3.3.0]octenylmethylacetate derivative represented by the above formula [I-e] obtained inthe above second step with lithium dialkylcuprate.

The lithium dialkylcuprate is a compound which is easily prepared byreacting copper (I) iodide with 3-butenyl lithium (as for thepreparative method thereof, see R. F. Cunico, Y. K. Han, J. Organomet.Chem., 174, 247 (1977)).

In carrying out this step, an ether solvent such as diethyl ether,tetrahydrofuran, dimethoxyethane, etc. may desirably be employed.

The reaction can proceed smoothly at -100° to 50° C.

The present invention is described in more detail by referring to thefollowing Reference examples and Examples.

REFERENCE EXAMPLE 1

To a solution of{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone}(707 mg, 1.44 mmol) dissolved in methylene chloride (7 ml) was addedzinc-titanium chloride-methylene bromide reagent (Zn-TiCl₄ -CH₂ Br₂/THF, 7.48 ml, about 1.3 equivalents) at room temperature. The mixturewas stirred at the same condition for 30 minutes so that the startingmaterials were all reacted. Subsequently, the mixture was poured intothe two layer system solution comprising ether-saturated aqueous sodiumhydrogencarbonate solution so as to stop the reation. Then, an etherlayer was separated from the mixture, and an aqueous layer was extractedwith ether. The combined ether layers were washed with a saturatedaqueous ammonium chloride solution and saturated saline solution, anddried with anhydrous magensium sulfate. Evaporation of the solvent,followed by purification through silica gel column chromatography toobtain{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene}(652 mg, Yield: 88%) as substantially colorless oily products.

IR (neat): 3080, 2930, 2850, 1650, 1460, 1360, 1250 cm⁻¹.

NMR δ (CDCl₃): 5.70 (m, 1H), 5.41 (m, 2H), 4.75-5.10 (m, 4H), 4.02 (m,1H), 3.76 (m, 1H), 2.00-2.70 (m, 6H), 1.40 (m, 8H), 0.88 (s, 21H), 0.02(s, 12H).

Mass m/z (%): 435 (M⁺ -57), 421, 393, 323, 303, 289, 229, 147, 75, 73.

REFERENCE EXAMPLE 2

To{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene}(700mg, 1.42 mmol) was added a THF solution (7.10 mmol, 14.2 ml) of9-borabicyclo[3.3.1]nonane (9-BBN) at room temperature, and the mixturewas stirred for 3 hours. Then, to the reaction system were graduallyadded dropwise a 6N-NaOH aqueous solution (6.9 ml) and a 30% H₂ O₂aqueous solution (5.8 ml) at room temperature, and the mixture wasstirred at 60° C. for 2 hours. The mixture was extracted with ether, andthe separated ether layer was washed with an aqueous sodium thiosulfatesolution and water. After dryness with anhydrous magensium sulfate,followed by evaporation of the solvent and purification through silicagel column chromatography to obtain{1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-cyclopentane}(502 mg, Yield: 67%) as colorless oily products.

IR (neat): 3350, 2930, 2850, 1460, 1360, 1250 cm⁻¹.

NMR δ (CDCl₃) 5.38 (m, 2H), 3.96 (m, 2H), 3.59 (m, 4H), 2.83 (m, 1H),2.16 (m, 3H), 1.10-1.80 (m, 15H), 0.87 (s, 21H), 0.04 (s, 12H).

Mass m/z (%): 471 (M⁺ -57), 453, 396, 379, 339, 325, 321, 247, 229, 75,73.

EXAMPLE 1

To a methylene chloride solution (5 ml) of oxalyl chloride (0.46 ml,5.40 mmol) was added dropwise a methylene chloride solution (4 ml) ofDMSO (0.83 ml, 11.7 mmol) at -78° C. for 5 minutes, and the mixture wasstirred at the same condition for 15 minutes. To the thus preparedmixture was added dropwise a methylene chloride solution (3 ml) of{1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxycyclopentane(475 mg, 0.900 mmol), and the mixture was further stirred at -78° C. for15 minutes. Under the same condition, triethylamine (2.50 ml, 18.0 mmol)was added thereto, then a cooling bath was removed and the mixture wasstirred for 15 minutes. Methylene chloride was distilled out underreduced pressure and to the resultant residue were added benzene (8 ml)and trifluoroacetic acid salt of dibenzylamine (220 mg, 0.900 mmol) andthe mixture was stirred at 70° C. for 4 hours. The mixture was dilutedwith ether, washed successively with an aquoues ammonium chloridesolution, a saturated aqueous sodium hydrogencarbonate solution and asaturated saline solution and dried with anhydrous magensium sulfate.After evaporation of the solvent, the residue was purifired throughsilica gel column chromatography to obtain{3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cisbicyclo[3.3.0]oct-2-ene}(441 mg, Yield: 97%) as substantially colorless oily product.

IR (neat): 2950, 2850, 1680, 1460, 1360, 1250 cm⁻¹.

NMR δ (CDCl₃) 9.82 (s, 1H), 6.73 (bs, 1H), 5.48 (m, 2H), 4.08 (m, 1H),3.76 (m, 1H), 3.24 (m, 1H), 1.10-2.80 (m, 14H), 0.87, 0.90 (2s, 21H),0.03 (s, 12H).

Mass m/z (%): 449 (M⁺ -57), 435, 359, 339, 317, 303, 202, 73.

EXAMPLE 2

{3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-transoctenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(18.9 mg, 0.0374 mmol) was mixed in a mixed solvent of aceticacid-water-tetrahydrofuran (3:1:1) (0.2 ml) and the mixture was stirredat 45° C. for 3 hours. After evaporation of the solvent under reducedpressure, to the residue was added a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. Theseparated organic layer was washed with a saturated saline solution anddried with anhydrous magensium sulfate. Evaporation of the solvent,followed by purification through silica gel column chromatography toobtain{3-formyl-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo-[3.3.0]oct-2-ene)(8.3 mg, Yield: 80%) as substantially colorless oily product.

IR (neat): 3400, 2950, 2850, 1680 cm⁻¹.

NMR δ (CDCl₃) 9.82 (s, 1H), 6.73 (bs, 1H), 5.45 (m, 2H), 4.10 (m, 1H),3.80 (m, 1H), 3.24 (m, 1H).

Mass m/z (%): 278 (M⁺), 260 (M⁺ -H₂ O).

REFERENCE EXAMPLE 3

In the method as described in Reference examples 1 and 2, the sameprocedures were carried out as in Reference examples 1 and 2 except that{2(R)-allyl-3(R)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone}(434 mg, 1 mmol) was employed as the starting material to obtain(1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-4(R)-tetrahydropyranyloxycyclopentane}(374 mg) at a yield of 80% as substantially colorless oily product.

IR (neat): 3350, 2930, 2850, 1450, 1365, 1200 cm⁻¹.

NMR δ (CDCl₃): 5.35 (m, 2H), 4.50 (m, 2H), 4.00 (m, 2H), 3.60 (m, 8H).

Mass m/z (%): 468 (M⁺), 450.

EXAMPLE 3

In the method as described in Example 1, the same procedures werecarried out in Example 1 except that{1(S)-hydroxymethyl-2(S)-(3'hydroxypropyl)-3(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-4(R)-tetrahydropyranyloxycyclopentane}(374 mg, 0.80 mmol) was employed as the starting material to obtain{3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(232 mg) at a yild of 65 % and as substantially colorless oily product.

IR (neat): 2950, 2850, 1680 cm⁻¹.

NMR δ (CDCl₃) 9.81 (s, 1H), 6.75 (bs, 1H), 5.44 (m, 2H), 4.50 (m, 2H),3.20-4.10 (m, 7H).

Mass m/z (%): 446 (M⁺), 361.

EXAMPLE 4

The reaction was carried out following the same procedures as inReference examples 1 and 2 and Example 1 by using{2(R)-allyl-3(R)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone}(868 mg, 2 mmol) to obtain(3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(446 mg, Overall yield: 50%) as substantially colorless oily product.

IR (neat): 2950, 2850, 1680 cm¹.

NMR δ (CDCl₃): 9.81 (s, 1H), 6.75 (bs, 1H), 5.44 (m, 2H), 4.50 (m, 2H),3.20-4.10 (m, 7H).

Mass m/z (%): 446 (M⁺), 361.

EXAMPLE 5

{3-Formyl-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(7.8 mg, 0.1 mmol) was dissolved in anhydrous methylene chloride (1 ml),and to the solution was added subsequently dihydropyrane (84 mg, 1 mmol)and catalytic amount of anhydrous p-toluenesulfonic acid and stirred atroom temperature for 5 minutes. After the reaction was stopped by addinga saturated aqueous sodium hydrogencarbonate solution, the mixture wasextracted with ether. The separated organic layer was washed with asaturated saline solution and dried with anhydrous magensium sulfate.Evaporation of the solvent, followed by purification through silica gelcolumn chromatography to obtain{3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(42.4 mg, Yield: 95%) as substantially colorless oily product. Spectrumdata thereof are agreed with those of the sample obtained in Example 3.

REFERENCE EXAMPLE 4

To a methylene chloride (7 ml) solution of{2(R)-allyl-3(R)-[[3'(R)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone}(354 mg, 0.72 mmol) was added a zinctitanium chloride-methylene bromidereagent (Zn-TiCl₄ -CH₂ Br₂ /THF, 3.74 ml, about 1.3 equivalents). Themixture was stirred at the same condition for 30 minutes so that thestarting materials were all reacted. Subsequently, the mixture waspoured into the two layer system solution comprising ether-saturatedaqueous sodium hydrogencarbonate solution so as to stop the reation.Then, an ether layer was separated from the mixture, and an aqueouslayer was extracted with ether. The combined ether layers were washedwith a saturated aqueous ammonium chloride solution and saturated salinesolution, and dried with anhydrous magensium sulfate. Evaporation of thesolvent, followed by purification through silica gel columnchromatography to obtain{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene}(326 mg, Yield: 88%) as substantially colorless oily products.

IR (neat): 3078, 2930, 2850, 1648, 1460, 1360, 1247 cm⁻¹.

NMR δ (CDCl₃): 5.70 (m, 1H), 5.40 (m, 2H), 4.70-5.05 (m, 4H), 4.02 (m,1H), 3.76 (m, 1H), 2.00-2.60 (m, 6H), 1.38 (m, 9H), 0.88 (s, 18H), 0.02(s, 12H).

Mass m/z (%): 433 (M⁺ -57), 419, 391.

REFERENCE EXAMPLE 5

To{2(R)-allyl-3(R)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene}(698 mg, 1.42 mmol) was added THF solution of 9-borabicyclo)3.3.1]nonane(9-BBN) (7.10 mmol, 14.2 ml) at room temperature, and the mixture wasstirred for 3 hours. Then, to the reaction system were gradually addeddropwise an aqueous 6N-NaOH solution (6.9 ml) and an aqueous 30% H₂ O₂solution (5.8 ml) at room temperature, and the mixture was stirred at60° C. for 2 hours. The reaction mixture was extracted with ether andthe extracted ether layer was washed with an aqueous sodium thiosulfatesolution and water. After dryness with anhydrous magensium sulfate,followed by evaporation of the solvent and purification the residuethrough silica gel column chromatography to obtain{1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxycyclopentane(442 mg, Yield: 59%) as colorless oily product.

IR (neat): 3345, 2920, 2850, 1456, 1360, 1246 cm⁻¹.

NMR δ (CDCl₃): 5.35 (m, 2H), 3.95 (m, 2H), 3.59 (m, 4H), 2.16 (m, 4H),1.10-1.80 (m, 16H), 0.87 (s, 18H), 0.04 (m, 12H).

Mass m/z (%): 469 (M⁺ -57), 451, 394, 377.

EXAMPLE 6

To a methylene chloride solution (5 ml) of oxalyl chloride (0.46 ml,5.40 mmol) was added dropwise methylene chloride solution (4 ml) of DMSO(0.83 ml, 11.7 mmol) at -78° C. for 5 minutes, and the mixture wasstirred at the same condition for 15 minutes. To the thus preparedmixture was added dropwise a methylene chloride solution (3 ml) of{1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxycyclopentane(473 mg, 0.900 mmol), and the mixture was further stirred at -78° C. for15 minutes. Under the same condition, triethylamine (2.50 ml, 18.0 mmol)was added thereto, then a cooling bath was removed and the mixture wasstirred for 15 minutes. Methylene chloride was distilled out underreduced pressure and to the resultant residue were added benzene (8 ml)and trifluoroacetic acid salt of dibenzylamine (220 mg, 0.900 mmol) andthe mixture was stirred at 70° C. for 4 hours. The mixture was dilutedwith ether, washed successively with an aquoues ammonium chloridesolution, a saturated aqueous sodium hydrogencarbonate solution and asaturated saline solution and dried with anhydrous magensium sulfate.After evaporation of the solvent, the residue was purifired throughsilica gel column chromatography to obtain{3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (385 mg, Yield: 85%) as substantially colorless oily product.

IR (neat): 2950, 2850, 1675, 1450, 1360, 1250 cm⁻¹.

NMR δ (CDCl₃) 9.82 (s, 1H), 6.72 (bs, 1H), 5.45 (m, 2H), 4.05 (m, 1H),3.76 (m, 1H), 3.23 (m, 1H), 1.10-2.80 (m, 15H), 0.87, 0.90 (2s, 18H),0.03 (s, 12H).

Mass m/z (%): 447 (M⁺ -57), 433, 357, 337, 315, 301, 200, 71.

EXAMPLE 7

{3-Formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(18.9 mg, 0.0374 mmol) was mixed in a mixed solvent of acetic acid-H₂O-tetrahydrofuran (3:1:1) (0.2 ml) and the mixture was stirred at 45° C.for 3 hours. After evaporation of the solvent under reduced pressure, tothe residue was added a saturated aqueous sodium hydrogencarbonatesolution and extracted with ethyl acetate. The separated organic layerwas washed with a saturated saline solution and dried with anhydrousmagensium sulfate. Evaporation of the solvent, followed by purificationthrough silica gel column chromatography to obtain{3-formyl-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(8.7 mg, Yield: 84 a substantially colorless oily product.

IR (neat): 3400, 2950, 2850, 1684 cm⁻¹.

NMR δ (CDCl₃): 9.81 (s, 1H), 6.74 (bs, 1H), 5.45 (m, 2H), 4.10 (m, 1H),3.80 (m, 1H), 3.23 (m, 1H).

Mass m/z (%): 276 (M⁺), 258 (M⁺ -H₂ O).

REFERENCE EXAMPLE 6

In the method as described in Reference examples 4 and 5, the sameprocedures were carried our as in Reference examples 4 and 5 except that{2(R)-allyl-3(R)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone}(432 mg, 1 mmol) was employed as the starting material to obtain{1(S)-hydroxymethyl-2(S)-(3',-hydroxypropyl)-3(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-tetrahydropyranyloxycyclopentane}(275 mg) at a yield of 74% as substantially colorless oily product.

IR (neat): 3350, 2930, 2850, 1450, 1365, 1200 cm⁻¹.

NMR δ (CDCl₃): 5.34 (m, 2H), 4.50 (m, 2H), 4.00 (m, 2H), 3.60 (m, 8H).

Mass m/z (%): 466 (M⁺), 448.

EXAMPLE 8

In the method as described in Example 3, the same procedures werecarried out as in Example 3 except that{1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1-trans-propenyl]-(R)-tetrahydropyranyloxycyclopentane}(275 mg, 0.74 mmol) was employed as the starting material to obtain(3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(223 mg) at a yield of 68 % as substantially colorless oily product.

IR (neat): 2950, 2850, 1680 cm⁻¹.

NMR δ (CDCl₃): 9.81 (s, 1H), 6.74 (bs, 1H), 5.45 (m, 2H), 4.48 (m, 2H),3.20-4.10 (m, 7H).

Mass m/z (%): 444 (M⁺), 359.

EXAMPLE 9

The reaction was carried out following the same procedures as inReference examples 4 and 5 and Example 8 by using(2(R)-allyl-3(R)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone}(864 mg, 2 mmol) to obtain(3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclo-pentyl-1'-transpropenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(408 mg, Overall yield: 46%) as substantially colorless oily product.

IR (neat): 2950, 2850, 1680 cm⁻¹.

NMR δ (CDCl₃): 9.81 (s, 1H), 6.74 (bs, 1H), 5.45 (m, 2H), 4.48 (m, 2H),3.20-4.10 (m, 7H).

Mass m/z (%): 444 (M⁺), 359.

EXAMPLE 10

{3-Formyl-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-transpropenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(27.6 mg, 0.1 mmol) was dissolved in anhydrous methylene chloride (1ml), and to the solution was added subsequently dihydropyrane (84 mg, 1mmol) and catalytic amount of anhydrous p-toluenesulfonic acid andstirred at room temperature for 5 minutes. After the reaction wasstopped by adding a saturated aqueous sodium hydrogencarbonate solution,the mixture was extracted with ether.

The separated organic layer was washed with a saturated saline solutionand dried with anhydrous magensium sulfate. Evaporation of the solvent,followed by purification through silica gel column chromatography toobtain×3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(39.5 mg, Yield: 89%) as substantially colorless oily product. Variousspectrum data thereof are agreed with those of the sample obtained inExample 8.

EXAMPLE 11

3-Carboxypropyltriphenylphosphonium bromide (321 mg, 0.748 mmol) wassuspended in THF (3.0 ml), and to the suspension was added potassiumt-butoxide (167 mg, 1.49 mmol) and the mixture was stirred at roomtemperature for 10 minutes. To the obtained ylid compound having reddishorange color was added a THF (1.5 ml) solution of{3-formyl-6(S)-[3'-t-butyldimethylsilyloxy-1'-transoctenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(189 mg, 0.374 mmol), and the mixture was stirred for 30 minutes. Themixture was diluted with ether, added a 10% aqueous HCl solution andafter it was confirmed that the mixture was acidic (pH=4), an etherlayer was separated therefrom. After the separated aqueous layer wasextracted with ether, the ether layers were combined, washed with asaturated aqueous NaCl solution and dried with anhydrous magensiumsulfate. After evaporation of the solvent, the resultant residue wasdissolved in small amount of ether and added thereof an ether solutionof diazomethane to obtain a methyl ester derivative. Evaporation of thesolvent, followed by purification and separation through silica gelcolumn chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(194 mg, Yield: 88%) as substantially colorless oily products.

IR (neat): 2950, 2850, 1750, 1460, 1360, 1250 cm⁻¹.

NMR δ (CDC13) 6.27 (d, J=16 Hz, 2/5H, trans), 6.02 (d, J=11 Hz, 3/5H,cis), 5.51 (m, 4H), 4.07 (m, 1H), 3.70 (m, 1H), 3.69 (s, 3H), 2.97 (m,1H), 1.10-2.70 (m, 16H), 0.87, 0.90 (2s, 21H), 0.03 (s, 12H).

Mass m/z (%): 590 (M⁺), 534, 533, 519, 458, 427, 401, 301, 75, 73.

[α]_(O) ²⁰ =-37° (c=0.614, CHCl₃).

EXAMPLE 12

To a THF (0.5 ml) solution of{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-3'(S)-t-butyldimethylsilyloxy-1'-transoctenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(31 mg, 0.05 mmol) was added a solution of tetrabutylammonium fluoridedissolved in THF (0.16 ml, 1M solution), and the mixture was stirred atroom temperature for 15 hours. After the reaction was stopped by addinga saturated aqueous ammonium chloride solution, THF was distilled outunder reduced pressure. The resultant aqueous layer was extracted withethyl acetate, and the separated organic layer was washed with asaturated saline solution and dried with anhydrous magensium sulfate.Evaporation of the solvent, followed by purification through silica gelcolumn chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(15 mg, Yield: 79%) as colorless caramel.

IR (neat): 3400, 2950, 1742 cm⁻¹.

NMR δ (CDCl₃) 6.30 (d, J=16 Hz, 1/3H, trans), 6.02 (d, J=11 Hz, 2/3H,cis), 5.60 (m, 3H), 5.40 (m, 1H), 4.10 (m, 1H), 3.80 (m, 1H), 3.70 (s,3H), 3.02 (m, 1H).

Mass m/z (%): 362 (M⁺, 7), 344 (44), 326 (19), 300 (37), 220 (54), 178(55), 168 (41), 43 (100).

[α]_(O) ²⁰ =35° (c=0.466, MeOH).

EXAMPLE 13

In the method as described in Example 11, the same procedures werecarried out as in Example 11 except that{3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-transoctenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(446 mg, 1 mmol) was employed as the starting material to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-transoctenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(477 mg, Yield: 90%) as substantially colorless oily product.

IR (neat): 2950, 2850, 1745 cm⁻¹.

NMR δ (CDCl₃): 6.25 (d, J=16 Hz, 1/3H, trans), 6.02 (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.60 (m, 2H), 3.40-4.10 (m, 6H), 3.69 (s, 3H), 2.97(m, 1H), 0.87 (t, J=7 Hz, 3H).

Mass m/z (%): 530 (M⁺), 499, 445.

EXAMPLE 14

{3-(4'-Methoxycarbonyl-1'-butenyl)-6-(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(470 mg, 0.89 mmol) was dissolved in a mixed solvent of acetic aicd (4.7ml), water (1.6 ml) and THF (1.6 ml), and heated at atmospherictemperature of 45° C. for 6 hours. After evaporation of acetic acidunder reduced pressure, to the residue was added a saturated aqueoussodium hydrogencarbonate solution and extracted with ethyl acetate. Theseparated organic alyer was washed with saturated saline solution, anddried with anhydrous magensium sulfate. Evaporation of the solvent,followed by purification through silica gel column chromatography toobtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (261 mg, Yield: 81%) as colorless caramel. Spectrum datathereof are agreed with those of the sample obtained in Example 12.

EXAMPLE 15

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(15 mg, 0.04 mmol) was dissolved in methanol (0.3 ml). To the solutionwas added a 10% aqueous sodium hydroxide solution (0.3 ml) at 0° C.After stirring at 0° C. for 16 hours, the mixture was neutralized with a10% aqueous hydrochloric acid solution under cooling. After evaporationof methanol under reduced pressure, the residue was adjusted to pH 3 to4 and extracted with ethyl acetate. The extract was dried with anhydrousmagnesium sulfate and distilled out the solvent to obtain(3-(4'-carboxy-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(14 mg, Yield: 100%) as colorless caramel.

IR (neat): 3350, 1720, 1090, 970 cm⁻¹.

NMR δ (CDCl₃): 6.34 (d, J=16 Hz, 1/3H), 6.06 (d, J=11 Hz, 2/3H), 5.65(m, 3H), 5.45 (m, 1H), 3.10 (m, 1H).

EXAMPLE 16

3-Carboxypropyltriphenylphosphonium bromide (321 mg, 0.748 mmol) wassuspended in THF (3.0 ml), and to the suspension was added potassiumt-butoxide (167 mg, 1.49 mmol) and the mixture was stirred at roomtemperature for 10 minutes. To the obtained ylid compound having reddishorange color was added THF (1.5 ml) solution of{3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(189 mg, 0.374 mmol), and the mixture was stirred for 30 minutes. Themixture was diluted with ether, added a 10% aqueous HCl solution andafter it was confirmed that the mixture was acidic (pH=4), an etherlayer was separated therefrom. After the separated aqueous layer wasextracted with ether, the ether layers were combined, washed with asaturated aqueous NaCl solution and dried with anhydrous magensiumsulfate. After evaporation of the solvent, the resultant residue wasdissolved in small amount of ether and added an ether solution ofdiazomethane to obtain a methyl ester derivative. Evaporation of thesolvent, followed by purification and separation through silica gelcolumn chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-propenyl]-7(R)-t-butyl-dimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(175 mg, Yield: 80%) as substantially colorless oily products.

IR (neat): 2950, 2850, 1745, 1460, 1358, 1240 cm⁻¹.

NMR δ (CDCl₃): 6.25 (d, J=16 Hz, 2/5H, trans), 6.01 (d, J=11 Hz, 3/5H,cis), 5.50 (m, 4H), 4.07 (m, 1H), 3.69 (m, 1H), 3.68 (s, 3H), 2.98 (m,1H), 1.10-2.70 (m, 17H), 0.87, 0.90 (2s, 18H), 0.03 (s, 12H).

Mass m/z (%): 588 (M⁺), 532, 531, 517.

[α]_(D) ²⁰ =-37° (c=1.618, CHCl₃).

EXAMPLE 17

To a THF (1.5 ml) solution of(3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(81 mg, 0.14 mmol) was added a solution of tetrabutylammonium fluoridedissolved in THF (0.42 ml, 1M solution), and the mixture was stirred atroom temperature for 16 hours. After the reaction was stopped by addinga saturated aqueous ammonium chloride solution, THF was distilled outunder reduced pressure. The resultant aqueous layer was extracted withethyl acetate, and the separated organic layer was washed with asaturated saline solution and dried with anhydrous magensium sulfate.Evaporation of the solvent, followed by purification through silica gelcolumn chromatography to obtain(3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-transpropenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(49 mg, Yield: 100%) as colorless caramel.

IR (neat): 3400, 1740, 1430, 1160, 1090, 965 cm⁻¹.

NMR δ (CDCl₃): 6.22 (d, J=16 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.13-5.74 (m, 4H, olefinic proton), 3.66 (s, 3H), 3.50-4.00 (m,2H), 3.02 (m, 1H).

Mass m/z (%): 360 (M⁺), 342 (M⁺ -H₂ O), 324 (M⁺ -2H₂ O), 298, 273.

[α]_(D) ²⁰ =-30° (c=1.16, MeOH).

EXAMPLE 18

In the method as described in Example 16, the same procedures werecarried out as in Example 16 except that{3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cisbicyclo[3.3.0]oct-2-ene}(408 mg, 0.92 mmol) was employed as the starting material to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(447 mg, Yield: 92%) as substantially colorless oily product.

IR (neat): 2950, 2850, 1744 cm⁻¹.

NMR δ (CDCl₃) 6.24 (d, J=16 Hz, 1/3H, trans), 6.01 (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.60 (m, 2H), 3.50-4.10 (m, 6H), 3.68 (s, 3H), 2.98(m, 1H).

Mass m/z (%): 528 (M⁺), 497, 443.

EXAMPLE 19

{3-(4'-Methoxycarbonyl-1'-butenyl)-6-(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(500 mg, 0.95 mmol) was dissolved in a mixed solvent of acetic acid (4.7ml), water (1.6 ml) and THF (1.6 ml), and heated at atmospherictemperature of 45° C. for 6 hours. After evaporation of acetic acidunder reduced pressure, to the residue was added a saturated aqueoussodium hydrogencarbonate solution and extracted with ethyl acetate. Theseparated organic alyer was washed with saturated saline solution, anddried with anhydrous magensium sulfate. Evaporation of the solvent,followed by purification through silica gel column chromatography toobtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(308 mg, Yield: 90%) as colorless caramel. Spectrum data thereof areagreed with those of the sample obtained in Example 17.

EXAMPLE 20

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-[3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(50 mg, 0.14 mmol) was dissolved in methanol (1.1 ml). To the solutionwas added a 10% aqueous sodium hydroxide solution (1.1 ml) at 0° C.After stirring at 0° C. for 16 hours, the mixture was neutralized with a10% aqueous hydrochloric acid solution under cooling. After evaporationof methanol under reduced pressure, the residue was adjusted to pH 3 to4 and extracted with ethyl acetate. The extract was dried with anhydrousmagensium sulfate and distilled out the solvent to obtain{3-(4'-carboxy-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(43 mg,

Yield: 89%) as colorless caramel.

IR (neat): 3350, 1715, 1085, 970 cm⁻¹.

NMR δ (CDCl₃): 6.32 (d, J=16 Hz, 1/3H), 6.04 (d, J=12 Hz, 2/3H), 5.64(m, 3H), 5.44 (m, 1H), 3.10 (m, 1H).

REFERENCE EXAMPLE 7

To a benzene (0.9 ml) solution of{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-transoctenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(48 mg, 0.081 mmol) was added RhCl(Ph₃ P)₃ (10 mg), and the mixture wasstirred, under hydrogen atmosphere (ordinary pressure), at roomtemperature for an hour and then at 45° C. for 1.5 hours. After thecatalyst was removed by passing short length silica gel column, theresultant residue was purifired again through silica gel columnchromatography to obtain 45 mg of colorless oily product. To the productwas added a THF solution (0.8 ml, 1M concentration) oftetrabutylammonium fluoride and the mixture was stirred at roomtemperature for 12 hours to remove silyl ether. Evaporation of thesolvent, followed by purification through silica gel columnchromatography to obtain(3-(4'-methoxycarbonylbutyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (20 mg, Yield: 69%).

IR (neat): 3400, 2970, 2930, 2870, 1742 cm⁻¹.

NMR δ (CDCl₃) 5.60 (m, 2H), 5.33 (bs, 1H), 4.12 (m, 1H), 3.80 (m, 1H),3.69 (s, 3H), 3.00 (m, 1H).

Mass m/z (%): 346 (M⁺ -H₂ O), 328, 315, 302, 275, 247, 232, 199, 193,180, 179.

REFERENCE EXAMPLE 8

{3-(4'-Metoxycarbonylbutyl)-6(S)-[3'(S)-hydroxy-1'-transoctenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(10 mg, 0.027 mmol) was dissolved in methanol (0.3 ml). To the solutionwas added a 10% aqueous sodium hydroxide solution (0.2 ml) at 0° C.After stirring at 0° C. for 9 hours, the mixture was neutralized with a10% aqueous hydrochloric acid solution under cooling. After evaporationof methanol under reduced pressure, the residue was adjusted to pH 3 to4 and extracted with ethyl acetate. After dryness with anhydrousmagensium sulfate, followed by evaporation of the solvent to obtain[9(0)-methano-Δ⁶(9α) -PGI₁ ] (10 mg, Yield: 100%).

IR (neat): 3350, 2910, 2850, 1700, 1450, 1250 cm⁻¹.

NMR δ (CDCl₃) 5.60 (m, 2H), 5.31 (bs, 1H), 4.11 (m, 1H), 3.80 (m, 1H),3.00 (m, 1H), 0.90 (t, J=6 Hz, 3H).

Mass (CI, NH₃) m/z: 368 (M₊ +NH₄).

Melting point: 73° to 79° C.

[α]_(D) ²⁰ =+16° (c=0.25, MeOH).

REFERENCE EXAMPLE 9

To a benzene (0.5 ml) solution of{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]-oct-2-ene}(15 mg, 0.041 mmol) was added RhCl(Ph₃ P)₃ (5 mg), and the mixture wasstirred, under hydrogen atmosphere (ordinary pressure), at roomtemperature for an hour and then at 45° C. for 1.5 hours. After thecatalyst was removed by passing short length silica gel column, theresultant residue was purifired again through silica gel columnchromatography to obtain 9 mg of colorless oily product. The thusobtained product was dissolved in methanol (0.1 ml). To the solution wasadded a 10% aqueous sodium hydroxide solution (0.1 ml) at 0° C. Afterstirring at 0° C. for 9 hours, the mixture was neutralized with a 10%aueous hydrochloric acid solution at 0° C. After evaporation of methanolunder reduced pressure, the residue was adjusted to pH 3 to 4 andextracted with ethyl acetate. After dryness with anhydrous magensiumsulfate followed by evaporation of the solvent to obtain{3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy(1S,5S)-cis-bicyclo3.3.0]oct-2-ene}(9 mg) as colorless solid. Spectrum data thereof are agreed with thoseof the sample obtained in Reference Example 8.

REFERENCE EXAMPLE 10

To a benzene (0.5 ml) solution of{3-(4'-carboxy-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(14 mg, 0.041 mmol) was added RhCl(Ph₃ P)₃ (5 mg), and the mixture wasstirred, under hydrogen atmosphere (ordinary pressure), at roomtemperature for an hour and then at 45° C. for 1.5 hours. After thecatalyst was removed by short length silica gel column, the resultantresidue was purifired again through silica gel column chromatography toobtain 6 mg of{3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-1'-trans-ocetenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}as colorless solid. Spectrum data thereof are agreed with those of thesample obtained in Reference Example 8.

REFERENCE EXAMPLE 11

To a benzene (0.9 ml) solution of{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(47 mg, 0.081 mmol) was added RhCl(Ph₃ P)₃ (10 mg), and the mixture wasstirred, under hydrogen atmosphere (ordinary pressure), at roomtemperature for an hour and then at 45° C. for 1.5 hours. After thecatalyst was removed by passing short length silica gel column, theresultant residue was purifired again through silica gel columnchromatography to obtain 42 mg of colorless oily product. To the productwas added a THF solution (0.8 ml, 1M concentration) oftetrabutylammonium fluoride and the mixture was stirred at roomtemperature for 12 hours to remove silyl ether. Evaporation of thesolvent, followed by purification through silica gel columnchromatography to obtain{3-(4'-methoxycarbonylbutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(17 mg, Yield: 60%).

IR (neat): 3400, 2960, 2880, 1740 cm⁻¹.

NMR δ (CDCl₃): 5.61 (m, 2H), 5.32 (bs, 1H), 3.85 (m, 2H), 3.67 (s, 3H),3.00 (m, 1H), 1.10-2.60 (m, 26H).

Mass m/z (%): 344 (M⁺ -18), 326 (M⁺ -36), 300, 275, 243, 232, 225, 199,193, 183, 181, 180, 179, 141, 119, 117, 105, 93, 91, 81, 79, 69, 67, 55,41.

REFERENCE EXAMPLE 12

{3-(4'-Metoxycarbonylbutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(10 mg, 0.027 mmol) was dissolved in methanol (0.3 ml). To the solutionwas added a 10% aqueous sodium hydroxide solution (0.2 ml) at 0° C.After stirring at 0° C. for 9 hours, the mixture was neutralized with a10% aqueous hydrochloric acid solution under cooling. After evaporationof methanol under reduced pressure, the residue was adjusted to pH 3 to4 and extracted with ethyl acetate. After the extract was dried withanhydrous magensium sulfate, then distilled out the solvent to obtain(3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(10 mg, Yield: 100%) as colorless solids. Recrystallization from ethylacetate-hexane of the solids yilded colorless powders having meltingpoint of 115° to 116° C.

IR (KBr): 3430 (OH), 2960, 1700, 1655 cm⁻¹.

NMR δ (CDCl₃): 5.60 (m, 2H), 5.32 (bs, 1H), 3.90 (m, 2H), 3.00 (m, 1H),1.00-2.70 (m, 25H).

Mass (CI, NH₃) m/z: 366 (M⁺ +NH₄).

REFERENCE EXAMPLE 13

To a benzene (0.5 ml) solution of{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-transpropenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(15 mg, 0.041 mmol) was added RhCl(Ph₃ P)₃ (5 mg), and the mixture wasstirred, under hydrogen atmosphere (ordinary pressure), at roomtemperature for an hour and then at 45° C. for 1.5 hours. After thecatalyst was removed by passing short length silica gel column, theresultant residue was purifired again through silica gel columnchromatography to obtain 8 mg of colorless viscous oil. The thusobtained oil was dissolved in methanol (0.1 ml). To the solution wasadded a 10% aqueous sodium hydroxide solution (0.1 ml) at 0° C. Afterstirring at 0° C. for 9 hours, the mixture was neutralized with a 10%aueous hydrochloric acid solution under cooling. After evaporation ofmethanol under reduced pressure, the residue was adjusted to pH 3 to 4and extracted with ethyl acetate. After dryness with anhydrous magensiumsulfate followed by evaporation of the solvent to obtain{3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(8 mg) as colorless solid. Spectrum data thereof are agreed with thoseof the sample obtained in Reference Example 12.

REFERENCE EXAMPLE 14

To a benzene (0.5 ml) solution of{3-(4'-carboxy-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-transpropenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(14 mg, 0.041 mmol) was added RhCl(Ph₃ P)₃ (5 mg), and the mixture wasstirred, under hydrogen atmosphere (ordinary pressure), at roomtemperature for an hour and then at 45° C. for 1.5 hours. After thecatalyst was removed by passing short length silica gel column, theresultant residue was purifired again through silica gel columnchromatography to obtain 7 mg of{3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-transpropenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}as colorless solid. Spectrum data thereof are agreed with those of thesample obtained in Reference Example 12.

EXAMPLE 21

To a toluene (3.5 ml) solution of{3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(420 mg, 0.83 mmol) was added diisobutylaluminum hydride (1.25 mmol,0.71 ml, 1.76M hexane solution) at -78° C. and the mixture was stirredfor 90 minutes. To the mixture was added dropwise methanol until thegeneration of hydrogen was stopped, and the mixture was diluted withether. To the mixture was further added a saturated saline solution andstirring was continued until an organic layer became transparent. Afteran ether layer was separated from the mixture, extraction of an aqueouslayer with ether was repeated. The separated ether layer and theextracts were combined and dried with anhydrous magensium sulfate. Afterevaporation of the solvent, the residue was purified through silica gelcolumn chromatography to obtain{3-hydroxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(373 mg, Yield: 88%) as substantially colorless oily product.

IR (neat): 3350 cm⁻¹.

NMR δ (CDCl₃): 5.47 (m, 3H), 4.13 (m, 3H), 3.73 (m, 1H), 2.97 (m, 1H).

Mass m/z: 451 (M⁺ -57)

EXAMPLE 22

In the method as described in Example 21, the same procedures werecarried out as in Example 21 except that{3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-transoctenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(370 mg, 0.83 mmol) was employed as the starting material to obtain(3-hydroxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(316 mg, Yield: 85%) as substantially colorless oily product.

IR (neat): 3345 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 3H), 4.55 (m, 2H), 4.10 (m, 3H), 3.50-4.00 (m,5H), 2.98 (m, 1H).

Mass m/z: 364 (M⁺ -84).

EXAMPLE 23

To a pyridine (1.5 ml) solution of{3-hydroxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(97 mg, 0.19 mmol) were added acetic anhydride (0.29 mmol, 27 μl) andcatalytic amount of 4-dimethylaminopyridine at room temperature, and themixture was stirred for 30 minutes under the same conditions. To themixture was added a saturated aqueous copper sulfate solution and themixture was extracted with ether. The separated ether layer was washedwith water and then dried with anhydrous magensium sulfate. Afterexaporation of the solvent, the residue was purified through silica gelcolumn chromatography to obtain{3-acetoxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo-[3.3.0]oct-2-ene}(104 mg, Yield: 100%) as colorless oily product.

IR (neat): 1755 cm⁻¹.

NMR δ (CDCl₃): 5.47 (m, 3H), 4.55 (s, 2H), 4.01 (m, 1H), 3.68 (m, 1H),2.93 (m, 1H), 2.05 (s, 3H).

Mass m/z: 493 (M⁺ -57).

EXAMPLE 24

In the method as described in Example 23, the same procedures werecarried out as in Example 23 except that{3-hydroxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(85 mg, 0.19 mmol) was employed as the starting material to obtain(3-acetoxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(93 mg, Yield: 100%) as substantially colorless oily product.

IR (neat): 1750 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 3H), 4.55 (m, 4H), 4.05 (m, 1H), 3.40-4.00 (m,5H), 2.91 (m, 1H), 2.05 (s, 3H).

Mass m/z: 406 (M⁺ -84).

EXAMPLE 25 To a suspension of cuprous iodide (163 mg, 0.85 mmol) inethyl ether (1.5 ml) was added freshly prepared 3-butenyl lithium (1.70mmol, 1,31 ml, 1.30M hexane solution) at -30° C., and the mixture wasstirred for 30 minutes. After the mixture was cooled to -78° C., anethyl ether (1 ml) solution of{3-acetoxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(213 mg, 0.39 mmol) was added thereto and the mixture was stirred for anhour at the same conditions. After further continuation of stirring atroom temperature for 0.5 hour, the reaction was stopped by adding asaturated aqueous ammonium chloride solution. The reaction mixture wasextracted with ether, and the separated ether layer was washed with asaturated saline solution and dried with anhydrous magensium sulfate.After evaporation of the solvent, the residue was purified throughsilica gel column chromatography to obtain{3-(4'-pentenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1R,5R)-cis-bicyclo[3.3.0]oct-2-ene}(154 mg, Yield: 73%) as substantially colorless oily product. The thusobtained product contained about 10% of{2-(3'-butenyl)-3-methylidene-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-(1S,5S)-cis-bicyclo[3.3.0]octane}.

IR (neat): 1645 cm⁻¹.

NMR δ (CDCl₃): 5.40-6.05 (m, 1H), 5.35 (m, 2H), 5.20 (bs, about 1H),4.90 (m, 2H), 4.00 (m, 1H), 3.60 (m, 1H), 2.90 (m, about 1H).

Mass m/z: 489 (M⁺ -57).

EXAMPLE 26

In the method as described in Example 25, the same procedures werecarried out as in Example 25 except that{3-acetoxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-ocetenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(191 mg, 0.39 mmol) was employed as the starting material to obtain{3-(4'-pentenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(133 mg, Yield: 70%) as substantially colorless oily product. The thusobtained product contained about 10% of{2-(3'-butenyl)-3-methylidene-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-(1S,5S)-cis-bicyclo[3.3.0]octane}.

IR (neat): 1645 cm⁻¹.

NMR δ (CDCl₃): 5.40-6.05 (m, 1H), 5.35 (m, 2H), 5.20 (bs, about 1H),4.90 (m, 2H), 4.55 (m, 2H), 4.00 (m, 1H), 3.40-3.70 (m, 5H), 2.90 (m,about 1H).

Mass m/z: 402 (M⁺ -84).

EXAMPLE 27

In the method as described in Example 21, the same procedures werecarried out as in Example 21 except that{3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(418 mg, 0.83 mmol) was employed as the starting material to obtain{3-hydroxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(372 mg, Yield: 86%) as substantially colorless oily product.

IR (neat): 3350 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 3H), 4.13 (m, 3H), 3.70 (m, 1H), 2.98 (m, 1H).

Mass m/z: 449 (M⁺ -57).

EXAMPLE 28

In the method as described in Example 21, the same procedures werecarried out as in Example 21 except that{3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cisbicyclo[3.3.0]oct-2-ene}(368 mg, 0.83 mmol) was employed as the starting material to obtain{3-hydroxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-transpropenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(306 mg, Yield: 83%) as substantially colorless oily product.

IR (neat): 3345 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 3H), 4.55 (m, 2H), 4.10 (m, 3H), 3.50-4.00 (m,5H), 2.98 (m, 1H).

Mass m/z: 362 (M⁺ -84).

EXAMPLE 29

In the method as described in Example 23, the same procedures werecarried out as in Example 23 except that{3-hydroxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(96 mg, 0.19 mmol) was employed as the starting material to obtain{3-acetoxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(103 mg, Yield: 100%) as colorless oily product.

IR (neat): 1755 cm⁻¹.

NMR δ (CDCl₃): 5.47 (m, 3H), 4.54 (s, 2H), 4.00 (m, 1H), 3.68 (m, 1H),2.92 (m, 1H), 2.05 (s, 3H).

Mass m/z: 492 (M⁺ -57).

EXAMPLE 30

In the method as described in Example 23, the same procedures werecarried out as in Example 23 except that{3-hydroxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(84 mg, 0.19 mmol) was employed as the starting material to obtain{3-acetoxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(91 mg, Yield: 100%) as substantially colorless oily product.

IR (neat): 1750 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 3H), 4.55 (m, 4H), 4.05 (m, 1H), 3.40-4.00 (m,5H), 2.91 (m, 1H), 2.05 (s, 3H).

Mass m/z: 404 (M⁺ -84).

EXAMPLE 31

In the method as described in Example 25, the same procedures werecarried out as in Example 25 except that{3-acetoxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(211 mg, 0.39 mmol) was employed as the starting material to obtain{3-(4'-pentenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(149 mg, Yield: 70%) as substantially colorless oily product. Thisproduct also contained about 10% of a substance formed by a reaction ofγ-attack.

IR (neat): 1645 cm⁻¹.

NMR δ (CDCl₃): 5.40-6.05 (m, 1H), 5.35 (m, 2H), 5.20 (bs, about 1H),4.90 (m, 2H), 4.00 (m, 1H), 3.60 (m, 1H), 2.90 (m, about 1H).

Mass m/z: 487 (M⁺ -57).

EXAMPLE 32

In the method as described in Example 25, the same procedures werecarried out as in Example 25 except that{3-acetoxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(211 mg, 0.39 mmol) was employed as the starting material to obtain{3-(4'-pentenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(131 mg, Yield: 70%) as substantially colorless oily product. Thisproduct also contained about 10% of a substance formed by a reaction ofγ-attack.

IR (neat): 1645 cm⁻¹.

NMR δ (CDCl₃): 5.40-6.05 (m, 1H), 5.35 (m, 2H), 5.20 (bs, about 1H),4.90 (m, 2H), 4.55 (m, 2H), 4.00 (m, 1H), 3.40-3.70 (m, 5H), 2.90 (m,about 1H).

Mass m/z: 400 (M⁺ -84).

REFERENCE EXAMPLE 15

To a THF (1.2 ml) solution of{3-(4'-pentenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(175 mg, 0.32 mmol) (Purity: about 90%) was added 9-BBN (0.42 mmol, 0.83ml, 0.5M THF solution) at 0° C., and the mixture was stirred for 5 hoursat the same conditions. After continuation of stirring at the roomtemperature for 0.5 hour, to the mixture were added a 6N NaOH aqueoussolution (0.21 ml) and a 30% hydrogen peroxide aqueous solution (0.18ml). After stirring at 60° C. for an hour, the mixture was diluted withwater and extracted with ether. The separated ether layer was washedwith a saturated aqueous sodium thiosulfate solution and a saturatedsaline solution and dried with anhydrous magensium sulfate. Afterevaporation of the solvent, the residue was purified through silica gelcolumn chromatography to obtain {3-(5'-hydroxypentyl)6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(145 mg, Yield: 81%) as substantially colorless oily product.

IR (neat): 3350 cm⁻¹.

NMR δ (CDCl₃): 5.47 (m, 2H), 5.24 (m, 1H), 4.05 (m, 1H), 3.64 (m, 3H),2.91 (m, 1H).

Mass m/z: 507 (M⁺ -57).

REFERENCE EXAMPLE 16

In the method as described in Reference Example 15, the same procedureswere carried out as in Reference Example 15 except that{3-(4'-pentenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(156 mg, 0.32 mmol) was employed as the starting material to obtain{3-(5'-hydroxypentyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(121 mg, Yield: 75%) as substantially colorless oily product.

IR (neat): 3400 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 2H), 5.24 (m, 1H), 4.60 (m, 2H), 4.05 (m, 1H),3.40-3.70 (m, 7H), 2.91 (m, 1H).

Mass m/z: 420 (M⁺ -84).

REFERENCE EXAMPLE 17

To{3-(5'-hydroxypentyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(22 mg, 0.039 mmol) was added a tetra-n-butylammonium fluoride solution(0.3 mmol, 0.3 ml, 1M THF solution), and the mixture was stirred at roomtemperature for 12 hours. The mixture was diluted with a saturatedsaline solution and then extracted with ethyl acetate. The separatedorganic layer was dried with anhydrous magensium sulfate and the solventwas distilled out therefrom. The residue was separated and purifiedthrough silica gel column chromatography (ethyl acetate:acetone=95:5) toobtain{3-(5'-hydroxypentyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(13 mg, Yield: 100%) as substantially colorless viscous liquid.

IR (neat): 3350 cm⁻¹.

NMR δ (CDCl₃): 5.52 (m, 2H), 5.28 (bs, 1H), 4.07 (m, 1H), 3.65 (m, 3H),2.97 (m, 1H).

Mass m/z: 318 (M⁺ -18)

REFERENCE EXAMPLE 18

{3-(5'-hydroxypentyl)-6(S)-[3'(S)-tetrahydropyranyloxy1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(20 mg, 0.040 mmol) was dissolved in a mixed solvent (1 ml) of aceticacid-water-THF (3:1:1), and the mixture was heated at 60° C. for 3hours. After the solvent was removed by distillation, to the residue wasadded small amount of a saturated aqueous sodium hydrogencarbonatesolution and the mixture was extracted with ethyl acetate. The separatedorganic layer was dried with anhydrous magnesium sulfate. Afterevaporation of the solvent, the residue was purified through silica gelcolumn chromatography to obtain{3-(5'-hydroxypentyl)-6(S)-[3'(S)-hydroxy-1'-trans-ocetnyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(13 mg, Yield: 100%) as substantially colorless viscous liquid. Each ofthe spectrum data thereof are completely agreed with those of the sampleobtained in Reference Example 17.

REFERENCE EXAMPLE 19

{3-(5'-Hydroxypentyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(12 mg, 0.036 mmol) was dissolved in a mixed solvent of acetone-H₂ O(1:4, 1.5 ml), and to the solution were added Pt, as a catalyst, whichwas obtained by reducing PtO₂ and sodium hydrogencarbonate (3.2 mg,0.038 mmol), and the mixture was stirred at 60° C. for 24 hours underoxygen gas stream. After the catalyst was removed by filtration and themixture was neutralized with a 10% HCl aqueous solution, acetone wasremoed by distillation. The residue was made acidic solution again withthe addition of a 10% HCl aqueous solution, the mixture was sufficientlyextracted with ethyl acetate. The extract was dried with anhydrousmagensium sulfate and distilled out the solvent to obtain(+)-9(0)-methano-Δ⁶(9α) -PGI₁ (8 mg, Yield: 61%) as substantiallycolorless viscous oily product.

IR (neat): 3350, 1700, 1450, 1250 cm⁻¹.

NMR δ (CDCl₃): 5.60 (m, 2H), 5.31 (bs, 1H), 4.11 (m, 1H), 3.80 (m, 1H),3.00 (m, 1H), 0.90 (t, J=6 Hz, 3H).

Mass (CI, NH₃) m/z: 368 (M⁺ +NH₄).

[α]_(D) ²⁰ =+16° (c=0.25, MeOH).

REFERENCE EXAMPLE 20

In the method as described in Reference Example 15, the same procedureswere carried out as in Reference Example 15 except that{3-(4'-pentenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(173 mg, 0.32 mmol) was employed as the starting material to obtain{3-(5'-hydroxypentyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(140 mg, Yield: 80%) as substantially colorless oily product.

IR (neat): 3350 cm⁻¹.

NMR δ (CDCl₃): 5.47 (m, 2H), 5.24 (m, 1H), 4.05 (m, 1H), 3.64 (m, 3H),2.91 (m, 1H).

Mass m/z: 505 (M⁺ -57).

REFERENCE EXAMPLE 21

In the method as described in Reference Example 16, the same procedureswere carried out as in Reference Example 16 except that{3-(4'-pentenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(154 mg, 0.32 mmol) (purity: about 90%) was employed as the startingmaterial to obtain{3-(5'-hydroxypentyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(115 mg, Yield: 72%) as substantially colorless oily product.

IR (neat): 3400 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 2H), 5.24 (m, 1H), 4.60 (m, 2H), 4.05 (m, 1H),3.40-3.70 (m, 7H), 2.91 (m, 1H).

Mass m/z: 418 (M⁺ -84).

REFERENCE EXAMPLE 22

In the method as described in Reference Example 17, the same procedureswere carried out as in Reference Example 17 except that{3-(5'-hydroxypentyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(21 mg, 0.039 mmol) was employed as the starting material to obtain{3-(5'-hydroxypentyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(12 mg, Yield: 100%) as substantially colorless viscous liquid.

IR (neat): 3350 cm⁻¹.

NMR δ (CDCl₃): 5.52 (m, 2H), 5.28 (bs, 1H), 4.07 (m, 1H), 3.65 (m, 3H),2.97 (m, 1H).

Mass m/z: 316 (M⁺ -18).

REFERENCE EXAMPLE 23

In the method as described in Reference Example 18, the same procedureswere carried out as in Reference Example 18 except that{3-(5'-hydroxypentyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(19 mg, 0.040 mmol) was employed as the starting material to obtain{3-(5'-hydroxypentyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(12 mg, Yield: 100%) as substantially colorless viscous liquid. Each ofthe spectrum data thereof are completely agreed with those of the sampleobtained in Reference Example 22.

REFERENCE EXAMPLE 24

In the method as described in Reference Example 19, the same procedureswere carried out as in Reference Example 19 except that{3-(5'-hydroxypentyl)-6(S)-[3'(S)-hydroxy3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(11 mg, 0.036 mmol) was employed as the starting material to obtain{3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(7 mg, Yield: 60%) as colorless white solid.

Melting point: 115° to 116° C. (recrystallized from ethylacetate-n-hexane).

IR (neat): 3430, 2960, 1700, 1655 cm⁻¹.

NMR δ (CDCl₃): 5.62 (m, 2H), 5.32 (bs, 1H), 3.90 (m, 2H), 3.00 (m, 1H).

Mass (CI, NH₃) m/z 366 (M⁺ +NH₄).

TEST EXAMPLE 1

In the compounds synthsized by the method as described above,9(0)-methano-Δ⁶(9α) -PGI₁, for example, has a biological activity asmentioned below. When the rabbit serum was employed, it depressd acohesion of platelets to be induced by adenosine diphosphate (ADP) at apotency of 1/10 to that of PGI₂, and it showed a potency of 1/2 to thatof PGI₂ when the human blood was employed. As for the effects to theblood pressure, when rat was examined, it showed the same effect as thatof PGI₂ and showed blood pressure depressing action at a dosage of 0.1μg/kg. An effect to the heart stroke frequencies thereof are almost thesame as that of PGI₂, and increasing of the heart stroke frequencieswere obserbed at a dosage of 1 μg/kg thereof in an experiment by usingrats. As for an anti-fester action, it showed an activity at a lowconcentration of 10⁻⁶ M in an experiment by using rabbit stomach, and itwas the same strength as that of PGE₂ . Cytotoxicity thereof areextremely weak and IC₅₀ =5 μg/ml.

TEST EXAMPLE 2

(+)-3-(4'-Carboxybutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-enehas biological activities as shown below. By using rabbit stomachepithelial cells, an experiment according to the mathod of Murota et.al. [K. Matsuoka, Y. Mitsui, and S. Murota, J. Pharm. Dyn., 5, 991(1982)] was carried out to obtain the result that it showed a remarkableanti-fester action at a low concentration of 0.5×10⁻⁶ M. This effect isthe same as that of PGE₂ which is representative prostaglandin havinganti-fester action. The above carbacyclin derivatives has no diarrheainductive effect whereas the PGE₂ induces heavy diarrhea.

We claim:
 1. A bicyclo[3.3.0]octene derivative represented by theformula: ##STR10## wherein R¹ : a straight, branched or cyclic alkylgroup or alkenyl group each having 5 to 10 carbon atoms;R² and R³ : eachrepresent a hydrogen atom or a protective group of a hydroxy group; andR⁴ : --CH═CH--(CH₂)₂ --COOR⁵ or --CH₂ R⁶ ;where R⁵ : a hydrogen atom oran alkyl group; and R⁶ : a hydroxy group, an acetyloxy group or abutenyl group.
 2. The bicyclo[3.3.0]octene derivative of claim 1,represented by the formula: ##STR11## wherein R¹ is a straight, branchedor cyclic alkyl group or alkenyl group each having 5 to 10 carbonatoms;R² and R³ each represent a hydrogen atom or a protective group ofa hydroxy group; and R⁶ is a hydroxyl group, an acetyloxy group or abutenyl group.
 3. The bicyclo[3.3.0]octene derivative of claim 1,represented by the formula: ##STR12## wherein R¹ is a straight, branchedor cyclic alkyl group or alkenyl group each having 5 to 10 carbonatoms;R² and R³ each represent a hydrogen atom or a protective group ofa hydroxy group; and R⁵ is a hydrogen atom or an alkyl group.